Bhattacharjee Biplab, Vijayasarathy Sandhya, Karunakar Prashantha, Chatterjee Jhinuk
Department of Biotechnology, PES Institute of Technology, Bangalore, India.
Asian Pac J Cancer Prev. 2012;13(11):5605-11. doi: 10.7314/apjcp.2012.13.11.5605.
In the last two decades, pioneering research on anti-tumour activity of saffron has shed light on the role of crocetin, picrocrocin and safranal, as broad spectrum anti-neoplastic agents. However, the exact mechanisms have yet to be elucidated. Identification and characterization of the targets of bioactive constituents will play an imperative role in demystifying the complex anti-neoplastic machinery.
In the quest of potential target identification, a dual virtual screening approach utilizing two inverse screening systems, one predicated on idTarget and the other on PharmMapper was here employed. A set of target proteins associated with multiple forms of cancer and ranked by Fit Score and Binding energy were obtained from the two independent inverse screening platforms. The validity of the results was checked by meticulously analyzing the post-docking binding pose of the picrocrocin with Hsp90 alpha in AutoDock.
The docking pose reveals that electrostatic and hydrogen bonds play the key role in inter-molecular interactions in ligand binding. Picrocrocin binds to the Hsp90 alpha with a definite orientation appropriate for nucleophilic attacks by several electrical residues inside the Hsp90-alpha ATPase catalytic site.
This study reveals functional information about the anti-tumor mechanism of saffron bioactive constituents. Also, a tractable set of anti-neoplastic targets for saffron has been generated in this study which can be further authenticated by in vivo and in vitro experiments.
在过去二十年中，关于藏红花抗肿瘤活性的开创性研究揭示了藏红花素、藏红花苦苷和藏红花醛作为广谱抗肿瘤药物的作用。然而，确切机制尚待阐明。生物活性成分靶点的鉴定和表征对于揭开复杂的抗肿瘤机制将起到至关重要的作用。
为了寻找潜在靶点，本研究采用了一种双重虚拟筛选方法，利用两个反向筛选系统，一个基于idTarget，另一个基于PharmMapper。从两个独立的反向筛选平台获得了一组与多种癌症相关并按拟合分数和结合能排序的靶蛋白。通过在AutoDock中仔细分析藏红花苦苷与热休克蛋白90α（Hsp90α）对接后的结合姿态，检验了结果的有效性。
对接姿态表明，静电和氢键在配体结合的分子间相互作用中起关键作用。藏红花苦苷以适合热休克蛋白90α-ATP酶催化位点内几个带电荷残基进行亲核攻击的特定方向与热休克蛋白90α结合。
本研究揭示了藏红花生物活性成分抗肿瘤机制的功能信息。此外，本研究还生成了一组可用于藏红花的易处理的抗肿瘤靶点，可通过体内和体外实验进一步验证。
